J Med Chem. 2020 Mar 12;63(5):2263-2281. doi: 10.1021/acs.jmedchem.9b01034. Epub 2019 Oct 18.
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of , a molecule with biochemical IC BACE2/BACE1 ratio of 47. Administration of resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, (AM-6494) was advanced to preclinical development.
β-位点淀粉样前体蛋白裂解酶 1（BACE1）是一种天冬氨酸蛋白酶，在大脑中淀粉样 β（Aβ）的产生中起关键作用，已被广泛研究作为治疗阿尔茨海默病（AD）的靶点。BACE2 是一种与 BACE1 结构相关的天冬氨酸蛋白酶，最近有报道称其参与黑素小体成熟和色素沉着。本文描述了一系列环丙基噻嗪类化合物作为有效和口服有效的 BACE1 抑制剂的开发。先导化合物优化导致了化合物 的发现，该化合物具有生化 IC BACE2/BACE1 比值为 47。在为期 13 天的小鼠色素减退研究中，给予 不会导致皮肤/毛发颜色改变，并在大鼠和猴子药效学模型中显示出强大且持续的 CSF 和脑 Aβ 水平降低。基于令人信服的数据包，化合物 （AM-6494）被推进到临床前开发阶段。
